Arsenical compound.



county, New York,

WALTER A. JACOBS, OE MOUNT VERNON, AND WADE H. BROWN, MICHAEL HEIDEIi- BERGER, AND LOUISE PEARCE, OF NEW YORK, N. Y., ASSIGNORS TO THE ROCKE- FELLER INSTITUTE FOR MEDICAL RESEARCH,

TION OF NEW YORK.

OF NEW YORK, N. Y., A. CORPORA- ARSENIGAL COMPOUND.

No Drawing.

To all whom it may concern:

Be it known that we, WALTER'A. J aoons,

Ph. D., residing at Mount. Vernon, Westchester county, New York, WADE H. BROWN, M. 1)., residing at Flushing, in the city of New York, borough of Queens, Queens MICHAEL HEIDELBERGER, Ph, D. residing in the city of New York, borough of Manhattan, county and State of New York, and LOUISE PEARCE, M. D., residing in the city of New York, borough of Manhattan, county and State of New York, all citizens of the United States, have jointly invented a new and Improved Arsenical Compound, of which the following is a specification.

In our co-pending applications, Serial Nos. 194,461 and 194,462, we have described two classes of arsenical compounds of use in the treatment of trypanosomal or spirochwtal infections. The first class was characterized as an aromatic arsonic acid possessing an a-aminoacylarylamin side chain, the aromatic nucleus containing the arsenic being joined to the oz-amino group in the side chain; the second class included substances characterized as aromatic arsinoxid possessing an a-aminoacylarylamin side chain, the aromatic nucleus containing the arsenic being joined to the oz-amino group in the side chain.

In ursuing further our chemical and biological experiments we. have, by passing to the arseno compounds of these substances, obtained substances with still greater therapeutic effects. This new class of compounds may be vchemically described as arsenophenylglycin-bis-arylamids, or, more generally, as N-(arsenoa l)-bis-oz-aminoacylary1- amins having the 0 lowing type formula:

Specification of Letters Patent.

Patented Esept. 24, 191%..

Application filedOctober 3, 1917. Serial No. 194,488.

(COOH), sulfonic acid (S0 11), or other salt forming groups either alone or in combinatlon with other groups. In the same way these substances may be chemically varied by like substitutions in the aryl nuclei containing the arseno (AszAs) residue or by altering the position of the arseno group with reference to the oi-aminoacylarylamin side chains.

In addition, the chain NHCH CONH- which joins each nucleus containing the arsenic with the two additional nuclei may be extended to include NHCHR CONH- in which B may be alkyl or aryl as explained in my previous co-pending applications Ser1al Nos. 194,461 and'194,462. These substances are not identical or analogous in a chemical or biological way to arsenophenylglycin, nor are they. derived therefrom. They represent an entirely new type of organic arseno compound.

These substances have been prepared by the action of strong reducing agents upon the corresponding arsonic acid or the arsinoxid derived from it. In articular that substance which is produce ,by the reduction of N(phenyl-p-arsonic acid) -glycyl-m aminophenol or the arsinoxid derived from it, both of which have been described in my co-pending applications Ser. Nos. 194,461 and 194,462, and which may be chemically designated as p-arsenophenyl lycin-bis-m.- oxyanilid with the following ormula:

A S==AS with 5 cc. of 48 per cent. hydriodic acid. This is then added to a solution prepared by pouring upon 75 grams of N-(phenyl-parsonic acid) -glycyl-m-aminophenol 1 liter of a mixture of 4 volumes of methyl alcohol and 1 volume concentrated hydrochloric acid and. warming to 3540 O. The reaction occurs at once with the separation of the dihydrochlorid of the arseno compound as a light yellow powder. After 15 minutes this is filtered 0E and Washed with a mixture of 4 volume parts of methyl alcohol and 1 of concentrated hydrochloric acid. The washing is then followed with water (boiled free of air and cooled), and'finally dilute sodium carbonate solution. The precipitate is then transferred to a vessel, treated with 500 cc. 2.5 per cent. NT-L OH, stoppered, and shaken until fully disintegrated and converted into the free base. This is then filtered, washed well with air-free water and dried in vacuum exsiccators. The product so obtained is owdered and preserved in sealed tubes rom which the air has been exhausted or containlng an inert nonoxidizing gas, such as nitrogen, carbon dioxid, or hydrogen. The yield is almost quantitative.

The product forms a yellowish powder which is insoluble in water and dilute ammonia or alkaline carbonate. It is easily soluble in methyl and ethyl alcohol and in the equivalent amount of normal potassium or sodium hydroxid, forming clear light yellow solutions. It melts at 160-70 C. Hydrochloric acid and sulfuric acid precipitate its alcoholic solution as the hydrochlorid and sulfate respectively. On oxidation with hydrogen peroxid it smoothly yields the original arsonic acid.

Example 2: 10 grams of N-(phenyl-parsinoxid)-glycyl-m-aminophenol are dissolved in 50 cc. of a mixture of 4' parts methyl alcohol and 1 part concentrated hydrochloric acid and treated with a solution of hypophosphorous acid obtained from 4 grams sodium hypophosphite as given in Examplel. The hy'drochlorid of the arseno me ias compound separates at once and is converted into the free base as in Example 1.

In the above examples, instead of using sodium hypophosphite, the solution can be made directly from hypophosphorous acid itself. Other strong reducing agents may also be employed. 7

The fore oing are a few examples of substances fal ing within the spirit and scope of our invention. It will be obvious to anyone skilled in the art that many variations in-the exact constitution of the substances described may be made without departing from the spirit and scope of our invention.

What we claim is:

1. As a new product, an N (arsenoaryl) bis-oe-aminoacylarylamin in which the arylamin nuclei carries an attached salt forming substitutent, substantially as described.

2. As a new product an N- (arsen'oaryl)- bis-glycylarylamin in which the arylamin nucleus carries an attached salt forming substituent, substantially as described.

3. As a new product, an N-(arsenoaryl)- bis-glycyloxyarylamin.

4. s a new product, an N-(arsenophenyl) -bis-glycyl-m-amino-phenol.

5. As a new product, N-(p-arsenophenyl) bis-glycyl-m-aminophenol, otherwise more shortly expressed as p-arsenophenylglycin-bis-m-oxyanilid, having the formula:

As As b IHCOCH NH HCHQCOI IE 6. As a new product, an N-(arsenoaryl)- bis-oz-aminoacylarylamin in which the ar 1 ac nuclei carry an attached salt forming su stituent, substantially as described.

WALTER A. JACOBS, PH. D. WADE H- BROWN, M. D. MICHAEL HEIDELBERGER, PH. D. LOUISE PEARCE, M. l). 

